Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being effected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
It is known that solid amorphous dispersions comprising a low-solubility drug in a polymer can increase the maximum concentration of drug that will dissolve in an aqueous solution in in vitro tests, or that will dissolve in body fluids such as those present in the gastrointestinal (GI) tract in in vivo tests, and, in turn, enhance the bioavailability of the drug. Solid dispersions of a drug in a matrix such as a polymer-can be prepared, for example, by forming a homogeneous solution or melt of the drug in matrix material, followed by solidifying the mixture by cooling or removal of solvent. Such solid dispersions of crystalline drugs have been known for more than two decades, and often show enhanced bioavailability when administered orally relative to compositions comprising undispersed crystalline drug.
One method for forming solid dispersions involves spray-drying-the drug and polymer together to form compositions of-drugs and polymers. For example, spray-dried compositions of drugs and polymers have been disclosed by Kai et al., 44 Chem. Pharm. Bull. 568-571 (1996); Takeuchi et al., 35 Chem. Pharm. Bull. 3800-3806 (1987); Dangprasirt et al., 21 Drug Development and Industrial Pharmacy: 2323-2337 (1995); Berde et al., U.S. Pat. No. 5,700,485; Wan et al., 18 Drug Development and Industrial Pharmacy 997-1011 (1992); and Akagi, U.S. Pat. No. 5,723,269.
Kai et al. disclose forming solid dispersion systems with an enteric polymer such as hydroxypropyl methylcellulose phthalate (HPMCP) or carboxymethyl ethylcellulose (CMEC), and with the non-enteric polymer hydroxypropylmethylcellulose (HPMC) by spray-drying. The drug is stated to be in an amorphous state. Kai et al. state that it is well-known that the crystallization of a drug within a polymer dispersion can occur during storage of the solid dispersion formulation, resulting in decreased bioavailability. The dispersion was reported to be stable for two months under desiccated storage conditions of elevated temperature (60° C.) in closed glass bottles, meaning that storage was under dry conditions.
Takeuchi et al. disclose an amorphous solid dispersion of tolbutamide in the enteric coating polymers EUDRAGIT® and HPMCP. The solid dispersions were prepared by spray-drying. The drug was stated to be poorly water-soluble. The authors state the amorphous state of the drug was well-maintained under dry conditions. However, the authors noted that the stability of the amorphous state of the drug in the solid dispersion was sensitive to the content of water around or in the sample.
U.S. Pat. Nos. 4,343,789, 4,404,183 and 4,673,564 all have the same disclosure of a sustained release composition of the vasodilator nicardipine comprising a solid amorphous dispersion of the drug in microcrystalline cellulose, polyethylene oxide, polyvinyl pyrrolidone and the cellulosic polymers hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate. However, the preferred method of forming the dispersion is by extensive and time-consuming ball-milling, and there is no recognition of the concentration-enhancing and drug-stabilizing properties of ionizable cellulosics for forming the drug dispersion.
It is also known to form solid dispersions containing polymers by other methods, such as by milling, grinding or solvent evaporation. For example, Nakamichi U.S. Pat. No. 5,456,923 discloses a process for forming solid dispersions using a twin-screw extruder. Nakamichi confirms that the resulting compositions are solid dispersions by noting the disappearance of peaks characterizing crystalline drug in X-ray diffraction analysis. Nakamichi does not discuss the stability of the drug in the dispersion.
Mechanical processes, such as that used by Nakamichi, have several drawbacks. First, the mechanical process normally does not achieve uniform homogeniety of the dispersion. After mixing, while the drug may be in an amorphous state, nevertheless the dispersion may be comprised of drug-rich regions with low concentrations of polymer. Second, the mechanical mixing process can degrade the drug. These two drawbacks are interrelated, since in order to increase the homogeneity of the dispersion, it is necessary to mix for longer periods of time or under more severe conditions of heat and pressure. Longer mixing times or severe conditions often result in greater amounts of degraded drug.
Yuasa et al., 42 Chem. Phaxm. Bull. 354-358 (1994) disclose a solid dispersion method used to improve bioavailability of slightly water-soluble drugs. The polymer is hydroxypropylcellulose (HPC). The HPC/drug dispersion is prepared by solvent evaporation, which is then ground and sieved. The authors report that the drug is in an amorphous state in the solid dispersion.
Nakano et al. U.S. Pat. No. 5,340,591 disclose solid dispersions of a sparingly soluble drug and cellulosic polymers. The dispersion is formed by mixing the drug and polymer while heating. The inventors state the drug is in an amorphous state.
Hasegawa et al., 33 Chem. Pharm. Bull. 388-91 (1985) disclose a solid dispersion prepared from the solvent evaporation method using the polymer HPMCP.
However, solid dispersions generally have not been used commercially to provide dosing of low-solubility drugs. As recognized by Kai-et al., Takeuchi et al., and Ford, J. L., 61 Pharm. Acta. Helv. 75 (1986), a problem encountered by dispersions of low-solubility drugs has been that these dispersions are susceptible to changes during storage and thus are not stable over time. Stability in this context refers to physical stability, that is the tendency for the drug present in a solid amorphous dispersion of drug in polymer to separate into drug-rich domains and/or to convert over time, at least partially, to the crystalline state. Most drug or pharmaceutical formulations are stored at ambient temperatures and relative humidity (atmospheric moisture) which can often be in excess of 50%. Such drug formulations should be as physically stable as possible in such an environment. Stability should be observed for at least one month, but ideally should be observed for a period of time of up to two years in order to provide unchanged bioavailability. Otherwise, such drug formulations require special handling and restrictions on prescriptions and on use by patients.
A major problem with current solid dispersions of drugs is that while the dispersions may show enhanced bioavailability of the low-solubility drug if administered shortly after preparation, bioavailability typically decreases over time in a typical storage environment. Such solid dispersions are often physically unstable in that the the drug present in the dispersion reverts to the crystalline form upon storage-particularly at elevated temperature and humidity. Accordingly, the dispersion cannot be used to provide proper dosing of the drug because the bioavailability of the drug changes over time.
Because of this, numerous researchers have sought to improve the stability of the dispersion. It has been widely thought that stable dispersions might best be obtained by using a matrix material in which the drug was highly soluble, thereby obtaining a thermodynamically stable solid solution. See, for example, Chino et al., 58 J. Pharm. Scab . 1505 (1969); Soukis et al., 79 International J. Pharmaceutics 120 (1992); Sheen et al., 118 International J. Pham . 221 (1995); and Gordano et al. 17 Drug Dev. & Induct. Pham. 1685 (1991). Unfortunately, this approach also has several drawbacks. First, it is difficult to find a particular polymer for each drug of interest to form a thermodynamically stable solid solution. Thermodynamic stability depends on interactions between the drug and polymer, which are generally not well understood and the number of polymers acceptable for use in oral dosage forms is quite limited. Second, thermodynamically stable dispersions of a drug and a polymer are typically only possible at low concentration of drug in the dispersion. This requires a large amount of polymer to be dosed with the drug which often makes dosing by conventional dosage form (such as pills, tablets, or capsules) impractical.
What is therefore desired is a composition comprising a dispersion of a low-solubility drug in a polymer that provides superior bioavailability, together with improved stability of the dispersion in typical storage environments, particularly for dispersions where the drug is present in concentrations above its equilibrium value.